2-232087546-C-T

Variant names:

• chr2-232087546-C-T
• rs73001172
• NM_152383.5:c.426C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_152383.5(DIS3L2):​c.426C>T​(p.Pro142Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 1,613,892 control chromosomes in the GnomAD database, including 213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (19 hom., cov: 31)
  • Exomes 𝑓: 0.014 (194 hom.)
• Consequence: DIS3L2 NM_152383.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.54
• Publications: 2 publications found

Genes affected

DIS3L2 (HGNC:28648): (DIS3 like 3'-5' exoribonuclease 2) The protein encoded by this gene is similar in sequence to 3'/5' exonucleolytic subunits of the RNA exosome. The exosome is a large multimeric ribonucleotide complex responsible for degrading various RNA substrates. Several transcript variants, some protein-coding and some not, have been found for this gene. [provided by RefSeq, Mar 2012]

DIS3L2 Gene-Disease associations (from GenCC):

• Perlman syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 2-232087546-C-T is Benign according to our data. Variant chr2-232087546-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.54 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0113 (1720/152042) while in subpopulation NFE AF = 0.0164 (1117/67982). AF 95% confidence interval is 0.0156. There are 19 homozygotes in GnomAd4. There are 859 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152383.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIS3L2	NM_152383.5	MANE Select	c.426C>T	p.Pro142Pro	synonymous	Exon 6 of 21	NP_689596.4
	DIS3L2	NM_001257281.2		c.426C>T	p.Pro142Pro	synonymous	Exon 6 of 14	NP_001244210.1
	DIS3L2	NM_001257282.2		c.426C>T	p.Pro142Pro	synonymous	Exon 6 of 7	NP_001244211.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIS3L2	ENST00000325385.12	TSL:5 MANE Select	c.426C>T	p.Pro142Pro	synonymous	Exon 6 of 21	ENSP00000315569.7
	DIS3L2	ENST00000409401.7	TSL:1	c.426C>T	p.Pro142Pro	synonymous	Exon 6 of 7	ENSP00000386594.3
	DIS3L2	ENST00000390005.9	TSL:1	n.426C>T		non_coding_transcript_exon	Exon 6 of 21	ENSP00000374655.5

Frequencies

GnomAD3 genomes AF: 0.0113 AC: 1723 AN: 151924 Hom.: 19 Cov.: 31

Gnomad AFR AF: 0.00261

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00747

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00327

Gnomad SAS AF: 0.00291

Gnomad FIN AF: 0.0278

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0164

Gnomad OTH AF: 0.0106

GnomAD2 exomes AF: 0.0113 AC: 2817 AN: 249502 AF XY: 0.0111

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.00478

Gnomad ASJ exome AF: 0.0108

Gnomad EAS exome AF: 0.00228

Gnomad FIN exome AF: 0.0284

Gnomad NFE exome AF: 0.0145

Gnomad OTH exome AF: 0.0127

GnomAD4 exome AF: 0.0138 AC: 20131 AN: 1461850 Hom.: 194 Cov.: 31 AF XY: 0.0135 AC XY: 9785 AN XY: 727216

African (AFR) AF: 0.00170 AC: 57 AN: 33480

American (AMR) AF: 0.00438 AC: 196 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0119 AC: 312 AN: 26136

East Asian (EAS) AF: 0.00222 AC: 88 AN: 39696

South Asian (SAS) AF: 0.00434 AC: 374 AN: 86238

European-Finnish (FIN) AF: 0.0288 AC: 1539 AN: 53418

Middle Eastern (MID) AF: 0.00329 AC: 19 AN: 5768

European-Non Finnish (NFE) AF: 0.0151 AC: 16775 AN: 1111996

Other (OTH) AF: 0.0128 AC: 771 AN: 60394

GnomAD4 genome AF: 0.0113 AC: 1720 AN: 152042 Hom.: 19 Cov.: 31 AF XY: 0.0116 AC XY: 859 AN XY: 74320

African (AFR) AF: 0.00260 AC: 108 AN: 41466

American (AMR) AF: 0.00746 AC: 114 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3468

East Asian (EAS) AF: 0.00328 AC: 17 AN: 5182

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4810

European-Finnish (FIN) AF: 0.0278 AC: 293 AN: 10544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0164 AC: 1117 AN: 67982

Other (OTH) AF: 0.00999 AC: 21 AN: 2102

Alfa AF: 0.0143 Hom.: 16

Bravo AF: 0.00881

Asia WGS AF: 0.00433 AC: 16 AN: 3478

EpiCase AF: 0.0143

EpiControl AF: 0.0129

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	2	Perlman syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	0.32
DANN	Benign	0.63
PhyloP100		-4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs73001172; hg19: chr2-232952256;